Alzheimer's disease, also referred to as Alzheimer's dementia or AD is a progressive neurodegenerative disorder that causes memory loss and serious mental deterioration. Diagnosticians have long sought a means to definitively identify AD during the lifetime of demented patients, as opposed to histopathological examination of brain tissue, which is the only present means available for rendering an ultimate diagnosis of AD. AD is the most common form of dementia, accounting for more than half of all dementias and affecting as many as 4 million Americans and nearly 15 million people worldwide. Dementia may start with slight memory loss and confusion, but advances with time reaching severe impairment of intellectual and social abilities. At age 65, the community prevalence of AD is between 1–2%. By age 75, the figure rises to 7%, and by age 85 it is 18%. The prevalence of dementia in all individuals over age 65 is 8%. Of those residing in institutions, the prevalence is about 50%, at any age.
The social impact of this disease is enormous, caused by the burden placed on caregivers, particularly in the latter stages of the disease. The substantial economic costs are largely related to supportive care and institutional admission. The rapidly increasing proportion of elderly people in society means that the number of individuals affected with AD will grow dramatically, therefore finding an early accurate diagnosis and a cure for AD is becoming an issue of major importance world wide.
When an individual is suspected of AD, several recommended tests are performed:(1) Mini Mental State Examination (MMSE)—an office-based psychometric test in the form of a Functional Assessment Questionnaire (FAQ) to examine the scale for functional autonomy, (2) Laboratory tests—complete blood count, measurement of thyroid stimulating hormone, serum electrolytes, serum calcium and serum glucose levels, (3) Neuroimaging—most commonly used is computed tomography (CT) which has a role in detecting certain causes of dementia such as vascular dementia (VaD), tumor, normal pressure hydrocephalus or subdural hematoma. However, neuroimaging is less effective in distinguishing AD or other cortical dementias from normal aging. In primary care settings, some suggest that CT could be limited to atypical cases, but others recommend routine scanning. Magnetic resonance imaging (MRI) currently offers no advantage over CT in most cases of dementia.
While Alzheimer's is the most common form of dementia, accounting for at least 60% of cases, diagnostic procedures for determining the exact cause of dementia, among more than 80 different species, is difficult at best.
In comparison to other disease areas, the field of dementia raises questions concerning the value of diagnosis, since there is currently no cure or effective therapy available. In dementia, as in all other branches of medicine, the certainty of a diagnosis has an important impact on the management of the patient. While AD cannot be cured at present time, there is symptomatic treatment available and the first drugs (acetylcholinesterase inhibitors) for the temporary improvement of cognition and behavior are now licensed by the U.S. Food and Drug Administration. Other drugs are at different stages of clinical trials:(1) Drugs to prevent decline in AD—DESFERRIOXAMINE, ALCAR, anti-inflammatory drugs, antioxidants, estrogen, (2) Neurotrophic Factors:NGF, (3) Vaccine:the recent most exciting report by Schenk et al. (Nature 1999;400:173–7) raises the hope of a vaccine for AD. Unfortunately, a percentage of patients cannot tolerate the pharmaceutical agents currently made available due to allergic reactions, drug interactions, genetic inability to properly metabolize the agent, or the like, and therefore are unable to utilize the medicinal advantages of these agents. In addition, the pharmaceutical agents themselves have limited therapeutic value. After a length of time, the agent no longer is able to function as intended due to the body's tolerance, resulting in the buildup of autoantibodies. In this case, alternate therapy to control the level of autoantibodies circulating in the body by periodic removal may increase the length of time of an agent's medicinal value.
The specificity of the various therapies thus require sophisticated diagnostic methodologies, having a high degree of sensitivity for AD, in order to insure their success.
Currently there are a multitude of tests available which aid in the diagnosis of AD. However, the only true existing diagnosis is made by pathologic examination of postmortem brain tissue in conjunction with a clinical history of dementia. This diagnosis is based on the presence in brain tissue of neurofibrillary tangles and of neuritic (senile) plaques, which have been correlated with clinical dementia. Neuritic plaques are made up of a normally harmless protein called amyloid-beta. Before neurons begin to die and symptoms develop, plaque deposits form between neurons early on in the disease process. The neurofibrillary tangles are interneuronal aggregates composed of normal and paired helical filaments and presumably consist of several different proteins. The internal support structure for brain neurons depends on the normal functioning of a protein called tau. In Alzheimer's disease, threads of tau protein undergo alterations that cause them to become twisted. The neurohistopathologic identification and counting of neuritic plaques and neurofibrillary tangles requires staining and microscopic examination of several brain sections. However, the results of this methodology can widely vary and is time-consuming and labor-intensive.
Given the ability of both current and prospective pharmacological therapies to forestall and/or reverse the onset and/or progress of Alzheimer's dementia, it behooves us to promulgate interim methodologies to delay the seemingly irreversible loss of cognitive function.
Various biochemical markers for AD are known and analytical techniques for the determination of such markers have been described in the art. As used herein the term “marker” “biochemical marker” or “marker protein” refers to any enzyme, protein, polypeptide, peptide, isomeric form thereof, immunologically detectable fragments thereof, or other molecule that is released from the brain during the course of AD pathogenesis. Such markers may include, but are not limited to, any unique proteins or isoforms thereof that are particularly associated with the brain.
The markers particularly targeted according to the method of the invention are glial fibrillary acidic protein (GFAP) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Glial fibrillary acidic protein is an intermediate filament protein found almost exclusively in astrocytes which, in adults, control the level of GFAP expression. Astrocytes are a major type of glial cell which perform a variety of structural and metabolic functions, such as processing neurotransmitters, controlling extracellular ion levels, regulating the direction and amount of nerve growth, maintaining the blood-brain barrier, and participating in immune reactions. As astrocytes transform from a resting state into a process-bearing reactive state during events such as aging, GFAP expression is up-regulated. Since levels have been found to increase in the brain tissue and cerebrospinal fluid in patients suffering from AD, it has been suggested that reactive astrocytes may contribute to the neuropathology of AD (Wallin et al. Dementia, 7, 267 (1996)). In the AD brain, the loss of synapses is associated with an increase in the number of GFAP-positive astrocytes. In addition, this loss of synapses appears to be related to the extent of reactive astrogliosis (Brun et al., Neurodegeneration, 4, 171 (1995)). GFAP is a major component of the gliotic scars which result from gliosis, and which may interfere with subsequent reinnervation.
Glyceraldehyde-3-phosphate dehydrogenase is ubiquitous in the cell, with the major fraction in the cytoplasm associated with cytoskeletal proteins and membranes, and small amounts in the nucleus (van Tuinen et al., J. Histochem. Cytochem., 35 (1987)). Its size has been characterized in the prior art as between 35,000 to 38,000 Daltons. As a monomer, GAPDH promotes tubulin polymerization, the major constituent of microtubules (Durrieu et al., Arch. Biochem. Biophys., 252, 32 (1987)). GAPDH has many enzymatic and binding activities including forming complexes with the C-terminal region of the amyloid precursor protein (Schulze et al., J. Neurochem., 60 (1993)). The disruption in binding of GAPDH to cytoskeletal elements such as tubulin can result in the alteration of neuronal morphology, function, and survival. Its involvement in the neurodegeneration during the development of AD has been hypothesized due to its link to amyloid plaques (Sunaga et al., Neurosci. Lett., 200, 2 (1995)).
The present inventors have theorized that when autoantibodies to GFAP and/or GAPDH proliferate in the bloodstream and cross the blood-brain barrier, they couple with GFAP positive cells, particularly astrocytic cells. In the presence of these autoantibodies, e.g. anti-GFAP antibodies, the macrophages become clumped around the astrocytes, thereby initiating the phagocytosis process. If it could be demonstrated that the concentration of these autoantibodies are a controlling factor in the initiation of astrocytosis, then it would be possible to alter the course of disease progression by modifying anti-GFAP or the like autoantibodies associated with biochemical markers for AD in the circulating sera, thus providing physicians with an additional method for possibly circumventing or delaying loss of cognition at an early stage in the pathogenesis of this disease.
Certain types of treatment devices are known to be useful for the removal of biological markers. Removal of these markers is also known to be a valuable tool for reducing the manifestations of disease progression.
What is lacking in the art is a method effective for altering the course of disease initiation/progression in living Alzheimer's dementia patients alone, or in conjunction with, the use of pharmaceutical agents.